There is now a consensus that postmenopausal estrogen replacement therapy (ERT) reduces morbidity and mortality from coronary heart disease (CHD). However, there is a continuing concern that the concurrent use of a progestogen (HRT) to protect the endometrium may reduce the cardiovascular benefits of ERT. This has stimulated interest in developing cardiovascular-safe (CV-safe) progestogens and/or alternative approaches to protect the endometrium and breast during estrogen replacement therapy. Progesterone does not diminish the cardiovascular benefits of ERT. However, it provides little or no additional beneficial effects on CV-risk, is associated with continued menstrual cycles and is not protective for the breast. Soy phytoestrogens (SPEs) may be an effective alternative approach to progestogen therapy. We have shown that SPEs have estrogen agonist effects on the cardiovascular system, but antagonizes the effects of ERT on mammary and endometrial tissue. Furthermore, SPEs combine with ERT to have additive beneficial effects on the cardiovascular system and on preservation of bone density. Thus, we hypothesize that, because of their estrogen agonist/antagonist properties, SPEs can obviate the need for progestogen therapy during ERT of postmenopausal females. To this end, our specific aims are: 1) To assess the potential contribution of increasing doses of SPEs to the putative beneficial cardiovascular (plasma lipoprotein concentrations, carbohydrate metabolism, vascular reactivity, hemodynamics) and bone (plasma markers of bone metabolism) effects of ERT treatment in postmenopausal subjects; 2) To identify the dose of SPEs that protects the mammary and endometrial tissue from ERT-induced cell proliferation and hyperplasia; 3) To identify and compare the potential additive beneficial effects of SPEs with those of progestogen treatment (MPA or progesterone) on cardiovascular and bone endpoints in postmenopausal subjects receiving ERT; and 4) To measure and compare the effects of SPE administration with those of MPA and progesterone, on mammary and endometrial hyperplasia in postmenopausal subjects receiving ERT.